Project Summary/Abstract Uncontrolled inflammation is a driver of diseases such as atherosclerosis, rheumatoid arthritis, and type 2 diabetes. Inflammation in adipose tissue leads to whole-body metabolic dysfunction, including insulin resistance in muscle and liver. Unfortunately, it has been difficult to identify genetic and metabolic components that link inflammation to whole-body insulin resistance. This project seeks to understand the communication between organs during chronic immune activation. The proposed project employs genetic approaches in the model organism Drosophila melanogaster to address how activation of the Toll signaling pathway in one organ, the larval fat body, can lead to cell- nonautonomous effects on peripheral organ function. The highly conserved insulin signaling pathway acts in the fly fat body to promote nutrient storage and growth of the whole animal. This organ also directs the response to infection via the innate immune Toll pathway. Activating Toll signaling in the fat body by infection or by transgenic expression of a constitutively active Toll receptor leads to decreased activation of the key downstream component of the insulin signaling pathway, Akt, impaired triglyceride storage, and reduced fat body cell growth. Toll signaling in the larval fat body leads to strong cell- nonautonomous phenotypes: increased circulating blood cell number, decreased whole-animal growth, reduced size of adult structures such as the wing, and disrupted heart function. These data and others lead us to hypothesize that these phenotypes arise due to whole-animal insulin resistance caused by fat body Toll signaling. However, the communication between the fat body to these other organs remains a black box. The objective of the project is to use genetic approaches to determine how fat body Toll signaling alters peripheral function. More specifically, the proposed aims will answer the following questions: 1) does rescuing fat body lipid homeostasis in animals with active Toll signaling restore insulin signaling in peripheral organs? 2) do circulating blood cells transduce effects of fat body Toll signaling to peripheral organs? and 3) will rescuing insulin signaling in peripheral organs, such as wing and heart, restore function in animals with active fat body Toll signaling? Discovery of mechanisms of communication between an inflamed tissue and the periphery in model organisms such as Drosophila melanogaster will pave the way for better understanding of human pathology in diseases caused and aggravated by inflammation, such as type 2 diabetes and cardiovascular disease.